CN101237852B - Liquid formulations - Google Patents

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CN101237852B
CN101237852B CN2006800286163A CN200680028616A CN101237852B CN 101237852 B CN101237852 B CN 101237852B CN 2006800286163 A CN2006800286163 A CN 2006800286163A CN 200680028616 A CN200680028616 A CN 200680028616A CN 101237852 B CN101237852 B CN 101237852B
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alkyl
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halogen
alkoxyl
phenyl
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CN101237852A (en
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V·格奥古西斯
W-Q·童
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Novartis AG
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Abstract

Disclosed is a concentrate for dilution comprising a S1P receptor agonist or a pharmaceutically acceptable salt thereof, propylene glycol and optionally glycerin. This formulation is adapted for patients in a difficult condition to swallow.

Description

Liquid preparation
The present invention relates to comprise the pharmaceutical composition of 1-phosphoric acid sphingol receptor modulators or agonist or its pharmaceutically acceptable salt.
1-phosphoric acid sphingol (hereinafter referred to as " S1P ") is a kind of natural blood fat.Now existing eight known S1P receptors, i.e. S1P1 to S1P8.S1P receptor modulators or agonists in general are the sphingol analog, and as the 2-amino the third-1 that 2-replaces, 3-glycol or 2-amino-propanol derivatives for example comprise the chemical compound of formula X group
Figure S2006800286163D00011
Wherein Z is H, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Phenyl, quilt that alkynyl, phenyl, OH replace are selected from halogen, C 3-8The C that 1-3 substituent group of the phenyl that cycloalkyl, phenyl and OH replace replaces 1-6Alkyl, or CH 2-R 4zR wherein 4zBe OH, acyloxy or formula (a) group
Figure S2006800286163D00012
Z wherein 1Directly be key or for O, be preferably O;
R 5zAnd R 6zBe H or the optional C that is replaced by 1,2 or 3 halogen atom independently of one another 1-4Alkyl;
R 1zBe OH, acyloxy or formula (a) group; And R 2zAnd R 3zBe H, C independently of one another 1-4Alkyl or acyl group.
Formula X group is the functional group that is connected to a certain group (it can be hydrophilic or lipophilic) as end group, and comprise one or more aliphatic, alicyclic, aromatic series and/or heterocyclic group, the molecule that makes acts in a plurality of 1-phosphoric acid sphingol receptors one as agonist, Z and R at least in the described molecule that obtains 1zOne of be formula (a) group or comprise formula (a) group.
S1P receptor modulators or agonist are the chemical compounds that acts on one or more 1-phosphoric acid sphingol receptors (as S1P1 to S1P8) as agonist.The agonist that is bonded to the S1P receptor for example can cause intramolecular heterotrimer G-albumen to be dissociated into G α-GTP and G β γ-GTP, and/or increases the phosphorylation and the downstream signal approach/kinase whose activation of the receptor that agonist occupies.
S1P receptor stimulating agent or regulator are to measuring in the experiment below can infra of the binding affinity of independent people S1P receptor:
At people S1P receptor S1P 1, S1P 2, S1P 3, S1P 4And S1P 5The S1P receptor stimulating agent or the regulator activity of last mensuration chemical compound.By to the inductive GTP[γ that is bonded to memebrane protein of chemical compound- 35S] carry out the activation degree of quantitative determination functional receptor, described memebrane protein is by the CHO or the RH7777 cell preparation of the transfection of the suitable people S1P receptor of stably express.Used analytical technology is SPA (scintillation proximity assay).In brief, at 50mM Hepes, 100mM NaCl, 10mMMgCl 2, 10 μ M GDP, 0.1% defat BSA and 0.2nM GTP[γ- 35S] (1200Ci/mmol) exist down, with the dissolved chemical compound serial dilution of DMSO and add to the memebrane protein (10-20 μ g/ hole) of the fixed expression S1P of SPA-pearl (Amersham-Pharmacia) receptor.At room temperature, hatch 120 minutes in the 96 hole titer plate after, by centrifugation step with unconjugated GTP[γ- 35S] separate.With the TOPcount plate read plate instrument (Packard) to membrane-bound GTP[γ- 35S] fluorescence of the SPA pearl that triggers quantizes.With standard curve match computed in software EC 50Value.In this experiment, S1P receptor modulators or agonist to the binding affinity of S1P receptor preferred＜50nM.
Preferred S1P receptor stimulating agent or regulator for example are except having S1P in conjunction with the chemical compound that also has the character of quickening lymphocyte homing the character, for example cause lymphopenia but do not cause the chemical compound that general immunity suppresses, described lymphopenia is to be caused from the distribution again (being preferably reversible) that is circulated to secondary lymphoid tissue by lymphocyte.Naive cell is isolated (Sequestered); CD4 in the blood and cd8 t cell and B cell are excited to move in lymph node (LN) and the PeyerShi speckle (PP).
Lymphocyte homing character can carefully reduce measuring by following blood lymph:
S1P receptor stimulating agent or regulator or solvent are administered orally to rat by tube feed.Obtain the tail blood that is used for the blood monitoring at first day, providing the benchmark individual values, and after administration, get tail blood 2,6,24,48 and 72 hours the time.In this experiment, when with for example＜during the dosed administration of 20mg/kg, S1P receptor stimulating agent or regulator reduce peripheral blood lymphocyte, for example reduce 50%.
The suitable S1P receptor modulators or the example of agonist for example are:
Disclosed chemical compound in EP627406A1, for example formula I chemical compound or its pharmaceutically acceptable salt or hydrate:
Figure S2006800286163D00031
R wherein 1(C for straight or branched 12-22) chain
It can contain in chain and is selected from following key or hetero atom: two keys; Triple bond; O; S; NR 6, R wherein 6Be H, C 1-4Alkyl, aryl-C 1-4Alkyl, acyl group or (C 1-4Alkoxyl) carbonyl; And carbonyl; And/or
It can have following substituent group: C 1-4Alkoxyl, C 2-4Alkene oxygen base, C 2-4Alkynyloxy group, aryl C 1-4Alkoxyl, acyl group, C 1-4Alkyl amino, C 1-4Alkylthio group, acyl amino, (C 1-4Alkoxyl) carbonyl, (C 1-4Alkoxyl)-carbonylamino, acyloxy, (C 1-4Alkyl) carbamoyl, nitro, halogen, amino, oximido, hydroxyl or carboxyl; Or
R 1For
Phenylalkyl, wherein alkyl is the (C of straight or branched 6-20) carbochain; Or
Phenylalkyl, wherein alkyl is the (C of straight or branched 1-30) carbochain, wherein said phenylalkyl
Replaced by following groups:
Choose (the C of the straight or branched that is replaced by halogen wantonly 6-20) carbochain,
Choose (the C of the straight or branched that is replaced by halogen wantonly 6-20) oxyalkyl chain,
(the C of straight or branched 6-20) alkene oxygen base,
Phenyl-C 1-14Alkoxyl, halogenophenyl-C 1-4Alkoxyl, phenyl-C 1-14Alkoxy-C 1-14Alkyl,
Phenoxy group-C 1-4Alkoxyl or phenoxy group-C 1-4Alkyl,
Optional by C 6-20The cycloalkyl-alkyl that alkyl replaces,
Optional by C 6-20The heteroaryl alkyl that alkyl replaces,
Heterocycle C 6-20Alkyl or
Optional by C 2-20The Heterocyclylalkyl that alkyl replaces,
And wherein
Alkyl group can contain:
In carbochain, be selected from following key or hetero atom: two keys, triple bond, O, S, sulfinyl, sulfonyl or NR 6, R wherein 6As defined above; With
Following substituent group: C 1-4Alkoxyl, C 2-4Alkene oxygen base, C 2-4Alkynyloxy group, aryl C 1-4Alkoxyl, acyl group, C 1-4Alkyl amino, C 1-4Alkylthio group, acyl amino, (C 1-4Alkoxyl) carbonyl, (C 1-4Alkoxyl)-carbonylamino, acyloxy, (C 1-4Alkyl) carbamoyl, nitro, halogen, amino, hydroxyl or carboxyl; And
R 2, R 3, R 4And R 5Be H, C independently of one another 1-4Alkyl or acyl group;
Disclosed chemical compound in EP 1002792A1, for example formula II chemical compound or its pharmaceutically acceptable salt or hydrate
Figure S2006800286163D00041
Wherein m is 1-9, and R ' 2, R ' 3, R ' 4And R ' 5Be H, C independently of one another 1-6Alkyl or acyl group;
Disclosed chemical compound in EP0778263A1, for example formula III chemical compound or its pharmaceutically acceptable salt or hydrate
Figure S2006800286163D00042
Wherein W is H; C 1-6Alkyl, C 2-6Thiazolinyl or C 2-6Alkynyl; Phenyl unsubstituted or that replaced by OH; R " 4O (CH 2) nOr C 1-6Alkyl, its 1-3 substituent group that is selected from following groups replaces: halogen, C 3-8The phenyl that cycloalkyl, phenyl and OH replace;
X is H, the perhaps unsubstituted or straight chained alkyl that contains p carbon atom that replaces, and the straight chain alkoxyl that contains (p-1) individual carbon atom of perhaps unsubstituted or replacement, 1-3 the substituent group that described alkyl or alkoxyl for example are selected from following group replaces: C 1-6Alkyl, OH, C 1-6Alkoxyl, acyloxy, amino, C 1-6Alkyl amino, acyl amino, oxo, halo C 1-61-3 the substituent group that the phenyl of alkyl, halogen, unsubstituted phenyl and replacement, the phenyl of described replacement are selected from following groups replaces: C 1-6Alkyl, OH, C 1-6Alkoxyl, acyl group, acyloxy, amino, C 1-6Alkyl amino, acyl amino, halo C 1-6Alkyl and halogen; Y is H, C 1-6Alkyl, OH, C 1-6Alkoxyl, acyl group, acyloxy, amino, C 1-6Alkyl amino, acyl amino, halo C 1-6Alkyl or halogen; Z 2For singly-bound or contain the straight-chain alkyl-sub-of q carbon atom,
P and q are the integer of 1-20 independently of one another, and prerequisite is 6≤p+q≤23, and m ' is 1,2 or 3, and n is 2 or 3,
R " 1, R " 2, R " 3And R " 4Be H, C independently of one another 1-4Alkyl or acyl group;
Disclosed chemical compound in WO02/18395, for example formula IVa or IVb chemical compound or its pharmaceutically acceptable salt or hydrate
Figure DEST_PATH_GSB00000045126300011
X wherein aBe O, S, NR 1sOr unsubstituted or by 1-4 halogen replace-(CH 2) Na-group; n aBe 1 or 2, R 1sBe H or (C 1-4) alkyl, this alkyl is unsubstituted or is replaced by halogen; R 1aBe H, OH, (C 1-4) alkyl or O (C 1-4) alkyl, wherein alkyl is unsubstituted or is replaced by 1-3 halogen; R 1bBe H, OH or (C 1-4) alkyl, wherein alkyl is unsubstituted or is replaced by halogen; Each R 2aBe independently selected from H or (C 1-4) alkyl, this alkyl is unsubstituted or is replaced by halogen; R 3aFor H, OH, halogen or wherein alkyl be O (C unsubstituted or that replaced by halogen 1-4) alkyl; And R 3bFor H, OH, halogen, wherein alkyl is unsubstituted or is replaced (C by hydroxyl 1-4) alkyl or wherein alkyl be O (C unsubstituted or that replaced by halogen 1-4) alkyl; Y aFor-CH 2-,-C (O)-,-CH (OH)-,-C (=NOH)-, O or S; And R 4aBe (C 4-14) alkyl or (C 4-14) thiazolinyl;
Disclosed chemical compound in WO02/06268AI, for example formula V chemical compound or its pharmaceutically acceptable salt, ester or hydrate
Figure S2006800286163D00061
Wherein, R 1dAnd R 2d respectivelyFrom being H or amino protecting group independently;
R 3dBe hydrogen or hydroxyl protecting group or following formula group
Figure S2006800286163D00062
R 4dBe C 1-4Alkyl;
n dInteger for 1-6;
X dFor ethylidene, ethenylidene, ethynylene, have formula D-CH 2(wherein D be carbonyl ,-CH (OH)-, O, S or N) group, aryl or the aryl that is replaced by three substituent groups at the most, described substituent group is selected from hereinafter defined group a;
Y dBe singly-bound, C 1-10Alkylidene, at the most by three C that substituent group replaced that are selected from group a or b 1-10Alkylidene, in the centre of its carbochain or the terminal C that contains O or S 1-10Alkylidene or in the centre of its carbochain or terminally contain O or S and this carbochain at the most by three C that substituent group replaced that are selected from group a or b 1-10Alkylidene;
R 5dBe hydrogen, C 3-6Cycloalkyl, aryl, heterocyclic group, at the most by three C that substituent group replaced that are selected from group a and b 3-6Cycloalkyl, be selected from the aryl that substituent group replaced of group a and b by three or at the most by three heterocyclic groups that substituent group replaced that are selected from group a and b at the most;
R 6dAnd R 7dBe H or the substituent group that is selected from group a independently of one another;
R 8dAnd R 9dBe H or the optional C that is replaced by halogen independently of one another 1-4Alkyl;
＜group a〉be halogen, low alkyl group, junior alkyl halides, lower alkoxy, lower alkylthio, carboxyl, elementary alkoxy carbonyl, hydroxyl, rudimentary aliphatic acidyl, amino, single low-grade alkyl amino, two-C 1-4Alkyl amino, acyl amino, cyano group or nitro; With
＜group b〉be C 3-6Cycloalkyl, aryl or heterocyclic group, they all can be chosen wantonly by three substituent groups that are selected from group a at the most and replace;
Prerequisite is to work as R 5aDuring for hydrogen, Y dBe singly-bound or linear C 1-10Alkylidene;
Disclosed chemical compound in JP-14316985 (JP2002316985), for example formula VI chemical compound or its pharmaceutically acceptable salt, ester or hydrate
Figure S2006800286163D00071
R wherein 1e, R 2e, R 3e, R 4e, R 5e, R 6e, R 7e, n e, X eAnd Y eAs disclosed in JP-14316985;
Disclosed chemical compound in WO 03/29184 and WO 03/29205, for example formula VII chemical compound or its pharmaceutically acceptable salt, solvate or hydrate
Figure S2006800286163D00072
X wherein fBe O, S, SO or SO 2
R 1fBe halogen, trihalomethyl group, OH, C 1-7Alkyl, C 1-4Alkoxyl, trifluoromethoxy, phenoxy group, cyclohexyl methoxyl group, pyridine radicals methoxyl group, cinnamyl oxygen base, naphthyl methoxyl group, phenoxymethyl, CH 2-OH, CH 2-CH 2-OH, C 1-4Alkylthio group, C 1-4Alkyl sulphinyl, C 1-4Alkyl sulphonyl, benzylthio, acetyl group, nitro or cyano group perhaps are phenyl, phenyl C 1-4Alkyl or phenyl-C 1-4Alkoxyl, above-mentioned each phenyl is optional by halogen, CF 3, C 1-4Alkyl or C 1-4Alkoxyl replaces;
R 2fBe H, halogen, trihalomethyl group, C 1-4Alkoxyl, C 1-7Alkyl, phenethyl or benzyloxy;
R 3fBe H, halogen, CF 3, OH, C 1-7Alkyl, C 1-4Alkoxyl, benzyloxy or C 1-4Alkoxy methyl;
R 4fAnd R 5fBe H or following formula group independently of one another
R wherein 8fAnd R 9fBe H or the optional C that is replaced by halogen independently of one another 1-4Alkyl; And
n fInteger for 1-4;
Disclosed chemical compound in WO03/062252A1, for example formula VIII chemical compound or its pharmaceutically acceptable salt, solvate or hydrate
Figure S2006800286163D00082
Wherein
Ar is a phenyl or naphthyl; m gAnd n gBe 0 or 1 independently of one another; A is selected from COOH, PO 3H 2, PO 2H, SO 3H, PO (C 1-3Alkyl) OH and 1H-tetrazolium-5-base; R 1gAnd R 2gBe H, halogen, OH, COOH or the optional C that is replaced by halogen independently of one another 1-4Alkyl; R 3gBe H or optional by the C of halogen or OH replacement 1-4Alkyl; Each R 4gBe halogen or the optional C that is replaced by halogen independently 1-4Alkyl or C 1-3Alkoxyl; And R gHas one of meaning that B and C indicated among the WO03/062252A1 separately respectively with M;
Disclosed chemical compound in WO 03/062248A2, for example formula IX chemical compound or its pharmaceutically acceptable salt, solvate or hydrate
Figure S2006800286163D00083
Wherein Ar is a phenyl or naphthyl; N is 2,3 or 4; A is COOH, 1H-tetrazolium-5-base, PO 3H 2, PO 2H 2,-SO 3H or PO (R 5h) OH, wherein R 5hBe selected from C 1-4Alkyl, hydroxyl C 1-4Alkyl, phenyl ,-CO-C 1-3Alkoxyl and-CH (OH)-phenyl, wherein said phenyl or phenyl group are what be optionally substituted; R 1hAnd R 2hBe H, halogen, OH, COOH or the optional C that is replaced by halogen independently of one another 1-6Alkyl or phenyl; R 3hFor H or optional by halogen and/ C that OH replaces 1-4Alkyl; Each R 4hBe halogen, OH, COOH, C independently 1-4Alkyl, S (O) 0,1 or 2C 1-3Alkyl, C 1-3Alkoxyl, C 3-6Cycloalkyloxy, aryl or aralkoxy, wherein said moieties can be chosen wantonly by 1-3 halogen and replace; And R hHas one of meaning that B and C indicated among the WO03/062248A2 separately respectively with M;
Disclosed chemical compound in WO 04/026817A, for example formula X chemical compound or its pharmaceutically acceptable salt, solvate or hydrate
Figure S2006800286163D00091
Wherein
R 1jBe halogen, trihalomethyl group, C 1-4Alkyl, C 1-4Alkoxyl, C 1-4Alkylthio group, C 1-4Alkyl sulphinyl, C 1-4Alkyl sulphonyl, aralkyl, optional phenoxy group or the aralkoxy that replaces; R 2jBe H, halogen, trihalomethyl group, C 1-4Alkyl, C 1-4Alkoxyl, aralkyl or aralkoxy; R 3jBe H, halogen, CF 3, C 1-4Alkyl, C 1-4Alkoxyl, C 1-4Alkylthio group or benzyloxy; R 4jBe H, C 1-4Alkyl, phenyl, optional benzyl or the benzoyl that replaces, or lower aliphatic C 1-5Acyl group; R 5jBe H, single halogenated methyl, C 1-4Alkyl, C 1-4Alkoxy methyl, C 1-4Alkylthio group methyl, ethoxy, hydroxypropyl, phenyl, aralkyl C 2-4, thiazolinyl or-alkynyl; R 6jAnd R 7jBe H or C independently of one another 1-4Alkyl; X jBe O, S, SO or SO 2And n jInteger for 1-4.
Disclosed chemical compound in WO 04/103306A, WO 05/000833, WO 05/103309 or WO 05/113330, for example formula XIa or XIb chemical compound with and N-oxide derivative or its prodrug or its pharmaceutically acceptable salt, solvate or hydrate
Figure S2006800286163D00092
Wherein
A kBe COOR 5k, OPO (OR 5k) 2, PO (OR 5k) 2, SO 2OR 5k, POR 5kOR 5kOr 1H-tetrazole radical-5-base, R 5kBe H or C 1-6Alkyl;
W kBe key, C 1-3Alkylidene or C 2-3Alkenylene;
Y kBe C 6-10Aryl or C 3-9Heteroaryl, their optional quilts are selected from halogen, OH, NO 2, C 1-6Alkyl, C 1-6The 1-3 of an alkoxyl group replaces; The C that halogen replaces 1-6The C that alkyl and halogen replace 1-6Alkoxyl;
Z kFor as in WO 04/103306A specified heterocyclic group, for example azetidine;
R 1kBe C 6-10Aryl or C 3-9Heteroaryl, they are chosen wantonly and are replaced by following group: C 1-6Alkyl, C 6-10Aryl, C 6-10Aryl C 1-4Alkyl, C 3-9Heteroaryl, C 3-9Heteroaryl C 1-4Alkyl, C 3-8Cycloalkyl, C 3-8Cycloalkyl C 1-4Alkyl, C 3-8Heterocyclylalkyl or C 3-8Heterocyclylalkyl C 1-4Alkyl; R wherein 1kIn any aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl can be replaced by the group that 1-5 is selected from following group: halogen, C 1-6Alkyl, C 1-6The C that alkoxyl and halogen replace 1-6The C that alkyl or halogen replace 1-6Alkoxyl;
R 2kBe H, C 1-6The C that alkyl, halogen replace 1-6Alkyl, C 2-6Thiazolinyl or C 2-6Alkynyl; And
R 3kOr R 4kBe H, halogen, OH, C independently of one another 1-6Alkyl, C 1-6The C that alkoxyl or halogen replace 1-6Alkyl or C 1-6Alkoxyl.
Formula I to XIb chemical compound can exist with free form or salt form.The example of the pharmaceutically acceptable salt of formula I to VI chemical compound comprises: the salt that becomes with mineral acid, for example hydrochlorate, hydrobromate and sulfate; The salt that becomes with organic acid, for example acetate, fumarate, maleate, benzoate, citrate, malate, mesylate and benzene sulfonate; Or in due course, the salt that becomes with metal, described metal for example are sodium, potassium, calcium and aluminum; The salt that becomes with amine, described amine for example are triethylamine; And the salt that is become with for example lysine amino diacid.Formula VII comprises with the example of the pharmaceutically acceptable salt of X chemical compound: the salt that becomes with mineral acid, for example hydrochlorate and hydrobromate; The salt that becomes with organic acid, for example acetate, trifluoroacetate, citrate, tartrate, mesylate and benzene sulfonate.The chemical compound of combination product of the present invention and salt comprise hydrate and solvate form thereof.
The acyl group of top indication can be R y-CO-group, wherein R yBe C 1-6Alkyl, C 3-6Cycloalkyl, phenyl or phenyl-C 1-4Alkyl.Unless otherwise indicated, alkyl, alkoxyl, alkenyl or alkynyl can be straight or brancheds.
Aryl can be a phenyl or naphthyl, is preferably phenyl.
In formula I chemical compound, work as R 1Carbochain for replace the time, it can be preferably by halogen, nitro, amino, hydroxyl or carboxyl substituted.When the phenylene that is optionally substituted when described carbochain interrupted, carbochain was preferably unsubstituted.When described phenylene group was replacement, it was preferably replaced by halogen, nitro, amino, methoxyl group, hydroxyl or carboxyl.
Preferred formula I chemical compound is R wherein 1For choosing wantonly by the C of nitro, halogen, amino, hydroxyl or carboxyl substituted 13-20The formula I chemical compound of alkyl, more preferably R wherein 1For by C 6-14The phenylalkyl and the alkyl group in the phenylalkyl of-alkyl chain (optional replaced by halogen) replacement are the optional C that is replaced by hydroxyl 1-6The chemical compound of-alkyl.More preferably, R 1Be phenyl-C 1-6Alkyl, this phenyl are preferably by (preferred straight chain) C of straight or branched 6-14Alkyl chain replaces.This C 6-14Alkyl chain can be at the ortho position, a position or para-position, preferably in para-position.
R 2To R 5All be preferably H separately.
Among the superincumbent formula V, " heterocyclic group " refers to contain 1-3 the first heterocyclic group of heteroatomic 5-7 that is selected from S, O and N.The example of these heterocyclic groups comprises the heteroaryl groups pointed out above and corresponding to the partially or completely heterocyclic compound of hydrogenant heteroaryl groups, for example furyl, thienyl, pyrrole radicals, azepine
Figure 2006800286163_0
Base (azepinyl), pyrazolyl, phonetic azoles base,
Figure 2006800286163_1
Azoles base, different
Figure 2006800286163_2
Azoles base, thiazolyl, isothiazolyl, 1,2,3- Di azoly, triazolyl, tetrazole radical, thiadiazolyl group, pyranose, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, THP trtrahydropyranyl, morpholinyl, thio-morpholinyl, pyrrolidinyl, pyrrole radicals, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl,
Figure 2006800286163_4
Oxazolidinyl, different Oxazolidinyl, thiazolidinyl or pyrazolidinyl.Preferred heterocyclic group is 5 or 6 yuan of heteroaryl groups, and most preferred heterocyclic group is morpholinyl, thio-morpholinyl or piperidyl group.
Preferred formula I chemical compound is 2-amino-2-myristyl-1, ammediol.Particularly preferred formula IS1P receptor stimulating agent is FTY720, i.e. 2-amino-2-[2-(4-octyl phenyl) ethyl] the third-1, the 3-glycol, it exists with free form or pharmaceutically acceptable salt form (hereinafter being called compd A), and hydrochlorate for example is as follows:
Figure S2006800286163D00111
Preferred formula II chemical compound is R ' wherein 2To R ' 5Be H and m separately and be 4 formula II chemical compound, i.e. 2-amino-2-{2-[4-(1-oxo-5-phenylpentyl) phenyl] ethyl } the third-1, the 3-glycol, it exists with free form or pharmaceutically acceptable salt form (hereinafter being called compd B), for example hydrochlorate.
Preferred formula III chemical compound is that wherein W is CH 3, R " 1To R " 3Be H, Z separately 2For ethylidene, X be heptan the oxygen base and Y be the formula III chemical compound of H, i.e. 2-amino-4-(4-oxygen in heptan base phenyl)-2-methyl-butanols, it exists with free form or pharmaceutically acceptable salt form (hereinafter being called Compound C), for example hydrochlorate.The R-enantiomer is particularly preferred.
Preferred formula IVa chemical compound is FTY720-phosphate (R 2aBe H, R 3aBe OH, X aBe O, R 1aAnd R 1bBe OH).Preferred formula IVb chemical compound is Compound C-phosphate (R 2aBe H, R 3bBe OH, X aBe O, R 1aAnd R 1bBe OH, Y aBe O and R 4aBe heptyl).Preferred formula V chemical compound is compd B-phosphate.
Preferred formula VI chemical compound is (2R)-2-amino-4-[3-(4-cyclohexyl oxygen Ji Dingji)-benzo [b] thiophene-6-yl]-2-methyl fourth-1-alcohol.
Preferred formula VII chemical compound for example is 2-amino-2-[4-(3-benzyloxy phenoxy group)-2-chlorphenyl] ethyl-1,3-third-glycol, 2-amino-2-[4-(benzyloxy thiophenyl)-2-chlorphenyl] ethyl-1,3-third-glycol, 2-amino-2-[4-(3-benzyloxy phenoxy group)-2-chlorphenyl] propyl group-1,3-third-glycol or 2-amino-2-[4-(benzyloxy thiophenyl)-2-chlorphenyl] propyl group-1,3-third-glycol.
Preferred formula X chemical compound for example is 2-amino-4-[4-(3-benzyloxy thiophenyl)-2-chlorphenyl]-2-methyl fourth-1-alcohol or 2-amino-4-[4-(3-benzyloxy thiophenyl)-2-chlorphenyl]-2-ethyl fourth-1-alcohol.
Preferred formula XIa chemical compound for example is 1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxy imino group)-ethyl]-2-ethyl-benzyl }-azetidine-3-formic acid or its prodrug.
Various known S1P receptor stimulating agents have structural similarity, and this causes producing and the suitable relevant problem of oral Preparation is provided.
Comprise S1P receptor modulators or agonist and can be for example by the child, since the patient of their disease and dysphagia or oral formulations that the gerontal patient is easy to swallow for required.For these patients, liquid dosage form is especially preferred, because this dosage form can be swallowed at an easy rate, instructs thereby described patient is easier to be obedient to the treatment of formulating for them.In addition, liquid preparation is to providing motility with the mg/kg dosed administration.
Yet, observed the compositions of the aqueous solution form that comprises S1P receptor modulators or agonist or its pharmaceutically acceptable salt, after preparation soon or can produce the crystal settling of medicine at lay up period.
In addition, when preparation was administered orally to the medicine of pediatric patients, medicine was restricted to and can only uses less kind of suitable vehicle, and for example this based composition should preferably not contain ethanol.
Find at present, at ambient temperature, comprise the compositions that the concentrate form to be used to dilute of propylene glycol and optional glycerol exists and to keep physically stable over a long time, for example above six months.
Therefore, the application provides the concentrate that is used to dilute, and this concentrate comprises S1P receptor modulators or agonist or its pharmaceutically acceptable salt, propylene glycol and optional glycerol.
Based on the gross weight of compositions, calculate by weight, the concentrate that is used to dilute of the present invention preferably comprises the S1P receptor stimulating agent of about 5-20%, 7-15% more preferably from about, for example about 10%.
Based on the gross weight of compositions, calculate by weight, the amount of the glycerol of the concentrate that is used for diluting of the present invention is generally 0-35%, for example 1-35%, about 5-25% for example.
Based on the gross weight of described compositions, calculate by weight, the amount of the propylene glycol of the concentrate that is used for diluting of the present invention is generally about 65-100%, for example about 65-99%, for example 75-95%.
The glycerol of the concentrate that is used for diluting of the present invention (when existing) is generally about 5: 95 to about 25: 75 with the ratio of propylene glycol, and for example about 5: 95,10: 90,15: 85,20: 80,25: 75, preferred about 25: 75.
Preferably, the concentrate that is used to dilute of the present invention has the quantitative flowing property of available syringe.
The concentrate that is used to dilute of the present invention can comprise one kind of multiple other excipient, for example other solvent, correctives and/or antiseptic.
Preferably, concentrate of the present invention be do not contain alcoholic acid.
Suitable correctives comprises citrus (citrus) correctives, and described citrus correctives comprises Fructus Pruni pseudocerasi, Fructus Fragariae Ananssae, Fructus Vitis viniferae, punch (punch), tutti-frutti, for example can obtain from Firmenich Inc..Based on the gross weight of described compositions, calculate by weight, the amount of the correctives of the concentrate that is used for diluting of the present invention is 0-0.5%.
Suitable preservatives comprises hydroxybenzoic acid derivative, for example methyl parahydroxybenzoate, propyl p-hydroxybenzoate or butyl p-hydroxybenzoate.Based on the gross weight of described compositions, calculate by weight, the amount of the antiseptic of the concentrate that is used for diluting of the present invention is 0.05-0.13%.
The concentrate that is used to dilute of the present invention can prepare with standard method, for example mixes by conventional.The methods availalbe that is known in the art is the method that is described in the following document: people such as L.Lachman, the theory and practice of industrial pharmacy (The Theory and Practice of IndustrialPharmacy), the third edition, 1986; People such as H.Sucker, Pharmazeutische Technologie, Thieme, 1991; Hagers Handbuch der pharmazeutischen Praxis, the 4th edition (Springer Verlag, 1971) and Remington ' s Pharmaceutical Sciences, the 13rd edition, (Mack Publ., Co., 1970) or later version.
On the one hand, the present invention relates to prepare the method for concentrate of the present invention, described method comprises and is dissolved in S1P receptor modulators or agonist or its pharmaceutically acceptable salt and optional other solvent, correctives and/or antiseptic in the propylene glycol and adds glycerol.
Before administration, the aequum of concentrate of the present invention for example quantitatively and with solvent is diluted with syringe.
The suitable dilution solvent comprises water; Soda pop (sparkling water); Fruit juice, for example orange juice or Sucus Mali pumilae; Soda water, for example cola, limeade (limeade) and lemonade (lemonade).
The ratio of concentrate and dilution solvent can for 1: 1 to surpassing 1: 10, be preferably above 1: 10.
On the other hand, the present invention also provides medicine box (pharmaceutical kit), and this medicine box comprises described concentrate and dilution solvent.
So the drug solution that forms can preferably use or (for example in 4 hours) use in the short period after formation immediately.
Concentrate of the present invention or the drug solution that is made by dilution can be used for the treatment of and prevent disease separately or with other active medicine combination, for formula I chemical compound, described disease is as disclosed disease in US 5604229, WO 97/24112, WO 01/01978, US 6004565, US 6274629 and JP-14316985; For formula VII chemical compound, described disease is as disclosed disease in WO 03/29184 and WO 03/29205; For formula X chemical compound, described disease is as disclosed disease in WO04/026817A; Perhaps for formula XIa and XIb chemical compound, described disease is as disclosed disease in WO 04/103306A, WO 05/000833, WO 05/103309 or WO 05/113330; The content of above-mentioned document is hereby incorporated by.
Particularly, concentrate of the present invention or be used for by the drug solution that dilution makes:
A) treatment and prevention organ or tissue transplant rejection are for example treated the receptor of heart, lung, the heart and lung, liver, kidney, pancreas, skin or corneal transplantation body and prevent graft versus host disease disease (for example occurring sometimes) after bone marrow transplantations; Particularly treat acute or chronic allograft rejection or xenograft rejection or in the transplanting of insulin-producing cells (for example islet cells);
B) treatment and prevention autoimmune disease or inflammatory diseases, for example multiple sclerosis, arthritis (for example rheumatoid arthritis), inflammatory bowel, hepatitis etc.;
C) treatment and prevention viral myocarditis and by the viral disease that viral myocarditis causes comprise hepatitis and AIDS.
Concentrate that is used to dilute or drug solution prepared therefrom can be administered to needs the immunosuppressant patient, the amount of dosage for for example disease or disease (can by administration S1P receptor modulators or agonist treatment) effectively being treated.The S1P receptor modulators of administration or the accurate amount of agonist or its pharmaceutically acceptable salt can in very large range change.Dosage can depend on the speed of particular compound, administration, used concrete concentrate or drug solution concentration, the disease for the treatment of or the character of disease and patient's sex, age and body weight.Dosage also may depend on existence, the nature and extent of any side effect that possibility described concentrate of concomitant dosing or pharmaceutical preparation occur.Usually, can be with 0.5-5mg S1P receptor modulators or agonist, compd A for example is administered to the adult patient of child or dysphagia.
Concentrate that is used to dilute or drug solution separately can with other immunosuppressant, steroid (for example prednisolone, methylprednisolone, dexamethasone, hydrocortisone etc.) or NSAID (non-steroidal anti-inflammatory drug) combination medicine-feeding.(one of active medicine is administration at first) can be carried out or carry out successively to the administration of the combination product of active medicine simultaneously.The dosage of the active medicine of combined therapy can depend on the effect effectiveness and the site of every kind of active component and be used for synergism between the medicine of combined therapy.
The preferred concentrate of oral administration or drug solution inclusion compound alite hydrochlorate (it is the S1P receptor modulators, for example is used for the treatment of multiple sclerosis).
The present invention is existing to be described with reference to following particular, and to the present invention without any restriction.
Embodiment 1-3
? Embodiment 1 Embodiment 2 Embodiment 3
The compd A hydrochlorate 11.12mg? 11.12mg? 5.56mg?
Glycerol 250mg? 10mg? 350mg?
Methyl parahydroxybenzoate -----? 0.5mg? -----?
The tutti-frutti correctives 2.5mg? 5mg? 2.5mg?
Propylene glycol Add to (qsad) 1ml in right amount Add to 1ml in right amount Add to 1ml in right amount
Compd A, correctives and antiseptic (if present) are dissolved in the propylene glycol with the amount that provides in the table.Glycerol (with given amount in the table) adds in the above-mentioned solution then.
Compositions can be stablized 6 months at ambient temperature at least.
Before the administration, with the concentrate of about 0.05ml to 1ml about 10ml or more water, fruit juice or soda water dilution.
According to aforesaid method, can prepare following compositions:
Embodiment 4-6
? Embodiment 4 Embodiment 5 Embodiment 6
The compd A hydrochlorate 2.78mg? 2.78mg? 1.39mg?
Glycerol 250mg? 10mg? 350mg?
Methyl parahydroxybenzoate -----? 0.5mg? -----?
The tutti-frutti correctives 2.5mg? 5mg? 2.5mg?
Propylene glycol Add to 1ml in right amount Add to 1ml in right amount Add to 1ml in right amount
Can not use correctives or use other correctives to prepare aforesaid same preparation.
Can not use glycerol to prepare aforesaid same preparation.

Claims (10)

1. be used to the concentrate that dilutes, based on the gross weight of compositions, calculate by weight, this concentrate comprises the S1P receptor modulators of 5-20% or the propylene glycol of agonist and 65-100%, and wherein S1P receptor modulators or agonist are selected from:
Formula I chemical compound or its pharmaceutically acceptable salt or hydrate:
Figure FSB00000045126200011
R wherein 1For
Phenylalkyl, wherein alkyl is the (C of straight or branched 6-20) carbochain; Or
Phenylalkyl, wherein alkyl is the (C of straight or branched 1-30) carbochain, wherein said phenylalkyl is replaced by following groups:
Choose (the C of the straight or branched that is replaced by halogen wantonly 6-20) carbochain,
Choose (the C of the straight or branched that is replaced by halogen wantonly 6-20) oxyalkyl chain,
(the C of straight or branched 6-20) alkene oxygen base,
Phenyl-C 1-14Alkoxyl, halogenophenyl-C 1-4Alkoxyl, phenyl-C 1-14Alkoxy-C 1-14Alkyl, phenoxy group-C 1-4Alkoxyl or phenoxy group-C 1-4Alkyl,
Optional by C 6-20The cycloalkyl-alkyl that alkyl replaces,
Optional by C 6-20The heteroaryl alkyl that alkyl replaces,
Heterocycle C 6-20Alkyl or
Optional by C 2-20The Heterocyclylalkyl that alkyl replaces,
And wherein
Alkyl group can contain:
In carbochain, be selected from following key or hetero atom: two keys, triple bond, O, S, sulfinyl, sulfonyl or NR 6, R wherein 6As defined above; With
Following substituent group: C 1-4Alkoxyl, C 2-4Alkene oxygen base, C 2-4Alkynyloxy group, aryl C 1-4Alkoxyl, acyl group, C 1-4Alkyl amino, C 1-4Alkylthio group, acyl amino, (C 1-4Alkoxyl) carbonyl, (C 1-4Alkoxyl)-carbonylamino, acyloxy, (C 1-4Alkyl) carbamoyl, nitro, halogen, amino, hydroxyl or carboxyl; And
R 2, R 3, R 4And R 5Be H, C independently of one another 1-4Alkyl or acyl group;
Formula II chemical compound or its pharmaceutically acceptable salt or hydrate
Figure FSB00000045126200021
Wherein m is 1-9, and R ' 2, R ' 3, R ' 4And R ' 5Be H, C independently of one another 1-6Alkyl or acyl group;
Formula III chemical compound or its pharmaceutically acceptable salt or hydrate
Figure FSB00000045126200022
Wherein W is H; C 1-6Alkyl, C 2-6Thiazolinyl or C 2-6Alkynyl; Phenyl unsubstituted or that replaced by OH; R " 4O (CH 2) nOr C 1-6Alkyl, its 1-3 substituent group that is selected from following groups replaces: halogen, C 3-8The phenyl that cycloalkyl, phenyl and OH replace;
X is H, the perhaps unsubstituted or straight chained alkyl that contains p carbon atom that replaces, and the straight chain alkoxyl that contains (p-1) individual carbon atom of perhaps unsubstituted or replacement, 1-3 the substituent group that described alkyl or alkoxyl for example are selected from following group replaces: C 1-6Alkyl, OH, C 1-6Alkoxyl, acyloxy, amino, C 1-6Alkyl amino, acyl amino, oxo, halo C 1-61-3 the substituent group that the phenyl of alkyl, halogen, unsubstituted phenyl and replacement, the phenyl of described replacement are selected from following groups replaces: C 1-6Alkyl, OH, C 1-6Alkoxyl, acyl group, acyloxy, amino, C 1-6Alkyl amino, acyl amino, halo C 1-6Alkyl and halogen;
Y is H, C 1-6Alkyl, OH, C 1-6Alkoxyl, acyl group, acyloxy, amino, C 1-6Alkyl amino, acyl amino, halo C 1-6Alkyl or halogen;
Z 2For singly-bound or contain the straight-chain alkyl-sub-of q carbon atom,
P and q are the integer of 1-20 independently of one another, and prerequisite is 6≤p+q≤23, and m ' is 1,2 or 3, and n is 2 or 3,
R " 1, R " 2, R " 3And R " 4Be H, C independently of one another 1-4Alkyl or acyl group;
Formula IVa or IVb chemical compound or its pharmaceutically acceptable salt or hydrate
Figure FSB00000045126200031
X wherein aBe O, S, NR 1sOr unsubstituted or by 1-4 halogen replace-(CH 2) Na-group;
n aBe 1 or 2, R 1sBe H or (C 1-4) alkyl, this alkyl is unsubstituted or is replaced by halogen;
R 1aBe H, OH, (C 1-4) alkyl or O (C 1-4) alkyl, wherein alkyl is unsubstituted or is replaced by 1-3 halogen;
R 1bBe H, OH or (C 1-4) alkyl, wherein alkyl is unsubstituted or is replaced by halogen;
Each R 2aBe independently selected from H or (C 1-4) alkyl, this alkyl is unsubstituted or is replaced by halogen;
R 3aFor H, OH, halogen or wherein alkyl be O (C unsubstituted or that replaced by halogen 1-4) alkyl;
And R 3bFor H, OH, halogen, wherein alkyl is unsubstituted or is replaced (C by hydroxyl 1-4) alkyl or wherein alkyl be O (C unsubstituted or that replaced by halogen 1-4) alkyl;
Y aFor-CH 2-,-C (O)-,-CH (OH)-,-C (=NOH)-, O or S;
And R 4aBe (C 4-14) alkyl or (C 4-14) thiazolinyl;
Formula VII chemical compound or its pharmaceutically acceptable salt, solvate or hydrate
Figure FSB00000045126200041
X wherein fBe O, S, SO or SO 2
R 1fBe halogen, trihalomethyl group, OH, C 1-7Alkyl, C 1-4Alkoxyl, trifluoromethoxy, phenoxy group, cyclohexyl methoxyl group, pyridine radicals methoxyl group, cinnamyl oxygen base, naphthyl methoxyl group, phenoxymethyl, CH 2-OH, CH 2-CH 2-OH, C 1-4Alkylthio group, C 1-4Alkyl sulphinyl, C 1-4Alkyl sulphonyl, benzylthio, acetyl group, nitro or cyano group perhaps are phenyl, phenyl C 1-4Alkyl or phenyl-C 1-4Alkoxyl, above-mentioned each phenyl are unsubstituted or by halogen, CF 3, C 1-4Alkyl or C 1-4Alkoxyl replaces;
R 2fBe H, halogen, trihalomethyl group, C 1-4Alkoxyl, C 1-7Alkyl, phenethyl or benzyloxy;
R 3fBe H, halogen, CF 3, OH, C 1-7Alkyl, C 1-4Alkoxyl, benzyloxy or C 1-4Alkoxy methyl;
R 4fAnd R 5fBe H or following formula group independently of one another
Figure FSB00000045126200042
R wherein 8fAnd R 9fBe H or C unsubstituted or that replaced by halogen independently of one another 1-4Alkyl;
And n fInteger for 1-4;
Formula X chemical compound or its pharmaceutically acceptable salt, solvate or hydrate
Figure FSB00000045126200043
Wherein
R 1jBe halogen, trihalomethyl group, C 1-4Alkyl, C 1-4Alkoxyl, C 1-4Alkylthio group, C 1-4Alkyl sulphinyl, C 1-4Alkyl sulphonyl, aralkyl, the phenoxy group or the aralkoxy that do not replace or replace;
R 2jBe H, halogen, trihalomethyl group, C 1-4Alkyl, C 1-4Alkoxyl, aralkyl or aralkoxy;
R 3jBe H, halogen, CF 3, C 1-4Alkyl, C 1-4Alkoxyl, C 1-4Alkylthio group or benzyloxy;
R 4jBe H, C 1-4Alkyl, phenyl, do not replace or replace benzyl or benzoyl, or lower aliphatic C 1-5Acyl group;
R 5jBe H, single halogenated methyl, C 1-4Alkyl, C 1-4Alkoxy methyl, C 1-4Alkylthio group methyl, ethoxy, hydroxypropyl, phenyl, aralkyl, C 2-4Thiazolinyl or-alkynyl;
R 6jAnd R 7jBe H or C independently of one another 1-4Alkyl; X jBe O, S, SO or SO 2
And n jInteger for 1-4;
Perhaps formula XIa chemical compound with and N-oxide derivative or its prodrug or its pharmaceutically acceptable salt, solvate or hydrate
Wherein
A kBe COOR 5k, OPO (OR 5k) 2, PO (OR 5k) 2, SO 2OR 5k, POR 5kOR 5kOr 1H-tetrazole radical-5-base, R 5kBe H or C 1-6Alkyl;
W kBe key, C 1-3Alkylidene or C 2-3Alkenylene;
Y kBe C 6-10Aryl or C 3-9Heteroaryl, their optional quilts are selected from halogen, OH, NO 2, C 1-6Alkyl, C 1-6The 1-3 of an alkoxyl group replaces; The C that halogen replaces 1-6The C that alkyl and halogen replace 1-6Alkoxyl;
Z kBe azetidine;
R 1kBe C 6-10Aryl or C 3-9Heteroaryl, they are unsubstituted or are replaced by following group: C 1-6Alkyl, C 6-10Aryl, C 6-10Aryl C 1-4Alkyl, C 3-9Heteroaryl, C 3-9Heteroaryl C 1-4Alkyl, C 3-8Cycloalkyl, C 3-8Cycloalkyl C 1-4Alkyl, C 3-8Heterocyclylalkyl or C 3-8Heterocyclylalkyl C 1-4Alkyl; R wherein 1kAny aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl be unsubstituted or replaced by the group that 1-5 is selected from following group: halogen, C 1-6Alkyl, C 1-6The C that alkoxyl and halogen replace 1-6The C that alkyl or halogen replace 1-6Alkoxyl;
R 2kBe H, C 1-6The C that alkyl, halogen replace 1-6Alkyl, C 2-6Thiazolinyl or C 2-6Alkynyl; And
R 3kOr R 4kBe H, halogen, OH, C independently of one another 1-6Alkyl, C 1-6The C that alkoxyl or halogen replace 1-6Alkyl or C 1-6Alkoxyl.
2. according to the concentrate of claim 1, wherein this concentrate comprises glycerol in addition.
3. according to the concentrate of claim 2, wherein glycerol and propylene glycol exist with 5: 95 to 25: 75 ratio.
4. according to any one concentrate among the claim 1-3, this concentrate comprises the S1P receptor stimulating agent, described S1P receptor stimulating agent is selected from 2-amino-2-[2-(4-octyl phenyl) ethyl] the third-1,3-glycol, 2-amino-2-[4-(benzyloxy thiophenyl)-2-chlorphenyl] ethyl-1,3-third-glycol or its corresponding phosphate ester and 1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxy imino group)-ethyl]-2-ethyl-benzyl)-azetidine-3-formic acid or its pharmaceutically acceptable salt.
5. according to any one concentrate among the claim 1-3, this concentrate comprises 2-amino-2-[2-(4-octyl phenyl) ethyl] the third-1,3-glycol or its pharmaceutically acceptable salt.
6. drug solution, this drug solution comprise water with 1: 1 to surpass 1: 10 dilution proportion according to any one concentrate among the claim 1-5.
7. according to the drug solution of the oral administration of claim 6.
8. be used for the treatment of purposes in needs immunosuppressant patient's the medicine according to the concentrate of any one among the claim 1-5 in preparation.
9. be used for the treatment of needs immunosuppressant patient or be used for the treatment of or prevent purposes in the medicine of organ or tissue's transplant rejection, autoimmune disease or inflammatory diseases in preparation according to the concentrate of any one among the claim 1-5.
According to claim 9 be used to prepare treatment and prevention multiple sclerosis, arthritis, inflammatory bowel, hepatitis, viral myocarditis or the purposes of the medicine of the viral disease that causes by viral myocarditis.
CN2006800286163A 2005-08-09 2006-08-08 Liquid formulations Expired - Fee Related CN101237852B (en)

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